Batf-mediated epigenetic control of effector CD8 + T cell differentiation

生物 转录因子 表观基因组 染色质 表观遗传学 转录组 效应器 表观遗传学 计算生物学 细胞生物学 遗传学 基因表达 基因 DNA甲基化
作者
Hsiao‐Wei Tsao,James J. Kaminski,Makoto Kurachi,R. Anthony Barnitz,Michael DiIorio,Martin W. LaFleur,Wataru Ise,Tomohiro Kurosaki,E. John Wherry,W. Nicholas Haining,Nir Yosef
出处
期刊:Science immunology [American Association for the Advancement of Science (AAAS)]
卷期号:7 (68) 被引量:30
标识
DOI:10.1126/sciimmunol.abi4919
摘要

The response of naive CD8 + T cells to their cognate antigen involves rapid and broad changes to gene expression that are coupled with extensive chromatin remodeling, but the mechanisms governing these changes are not fully understood. Here, we investigated how these changes depend on the basic leucine zipper ATF-like transcription factor Batf, which is essential for the early phases of the process. Through genome scale profiling, we characterized the role of Batf in chromatin organization at several levels, including the accessibility of key regulatory regions, the expression of their nearby genes, and the interactions that these regions form with each other and with key transcription factors. We identified a core network of transcription factors that cooperated with Batf, including Irf4, Runx3, and T-bet, as indicated by their colocalization with Batf and their binding in regions whose accessibility, interactions, and expression of nearby genes depend on Batf. We demonstrated the synergistic activity of this network by overexpressing the different combinations of these genes in fibroblasts. Batf and Irf4, but not Batf alone, were sufficient to increase accessibility and transcription of key loci, normally associated with T cell function. Addition of Runx3 and T-bet further contributed to fine-tuning of these changes and was essential for establishing chromatin loops characteristic of T cells. These data provide a resource for studying the epigenomic and transcriptomic landscape of effector differentiation of cytotoxic T cells and for investigating the interdependency between transcription factors and its effects on the epigenome and transcriptome of primary cells.
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